Clomiphene is an active pharmaceutical ingredient used as ovulatory stimulant to treat ovulatory dysfunction and polycystic ovary syndrome.
Clomiphene has chemical name Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl and it is a mixture of the geometric isomers trans-Clomiphene of chemical formula (I) and cis-Clomiphene of chemical formula (II):

The pharmaceutical products currently on the market containing Clomiphene, typically as monocitrate salt, comprise Clomiphene having the following composition: from 50% to 70% of trans-clomiphene and from 30% to 50% of cis-Clomiphene.
Trans-Clomiphene of chemical formula (I), also named Enclomiphene or E-Clomiphene, as monocitrate salt, i.e. trans-Clomiphene monocitrate or Enclomiphene citrate which is Enclomiphene citrate (1:1), having formula (III):
is currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it is also said that trans-Clomiphene, i.e. Enclomiphene, could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.
The U.S. Pat. No. 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.
In the later publication Acta Cryst. (1976), B32, pag. 291-293, the geometric isomery has been definitely established by single crystal X-Ray diffraction.
Finally, in the publication “Analytical profiles of drug substances and excipients”, vol. 25, (1998), pag. 85-121, in particular at pag. 99, it is stated that prior to 1976 the cis stereochemistry was wrongly assigned to the trans-isomer of Clomiphene (E-Chlomiphene or Enclomiphene), and only after the above publication on Acta Cryst. the correct geometric isomery has been definitively assigned.
These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of U.S. Pat. No. 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent, as confirmed by 2D H-NMR analysis (NOESY experiment). Thus, Example 31 of U.S. Pat. No. 3,848,030, provides, at the end, Enclomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 133-135° C. Example 32, instead provided Cis-Clomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 120-126° C.
Thus, with the aim of preparing Enclomiphene citrate, whole experiment 31 of U.S. Pat. No. 3,848,030 has been reworked also carrying out the crystallization of the product form a mixture of ethyl ether and ethanol, hence providing a not crystalline solid with two DSC peaks respectively at 114° C. and 188° C., although the starting material used for the reworking example was quite a pure substance (see notes below related to the salt of trans-Clomiphene salt with racemic binaphthyl-phosphoric acid), and having a substantially the same chemical purity of that used in the prior art experiment.
The U.S. Pat. No. 2,914,563, in example 3, and the recent PCT application WO2014/031177, in example 1, disclose a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1-p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethylene hydrochloride with N-chlorosuccinimmide in dry chloroform under reflux.
Khimiko-Farmatsevticheskii Zhurnal (1984), 18(11), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 11, pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of Clomiphene citrate and some intermediates of its synthesis) discloses the trans-isomer of Clomiphene citrate, i.e. Enclomiphene citrate, characterized by:
1H-NMR (MeOD) d 7.4-6.7 (m, 14H); 4.27 (t, 2H, —OCH2); 3.51 (t, 2H, CH2—N); 3.28 (q, 4H, 2xN-CH2)); 2.73 (2H); 2.78 (2H); 1.31 (t, 6H, 2xN—C—CH3)) Melting point: 138-139° C. (98% purity by GLC);
IR spectrum, v cm−1 (suspension in mineral oil): 3640, 3430, 1720, 1710 (citrate), 1600-1555 (broad band, stilbene system); 750.
UV spectrum: λ max=243 nm, ε 21,800 and λ max 300 nm, ε 11,400.
According to our experimental studies, these prior art methods for the preparation of Clomiphene and, in particular, of trans-Clomiphene, suffer from drawbacks related to unknown impurities which can contaminate the final product Clomiphene.
Moreover, Enclomiphene citrate was described in literature with different melting points, in particular, 133-135° C. and 138-139° C. Said solid forms of Enclomiphene citrate fail to comply with stabilities studies and furthermore show relatively poor solubility in water either in neutral or acid pH.
Example 31 of U.S. Pat. No. 3,848,030 does not disclose any solid form of Enclomiphene base, i.e. as free base, as well as example 32 does not disclose any form of cis-Clomiphene base.
A crystalline form of Enclomiphene base appears to be described in only one article: Khimiko-Farmatsevticheskii Zhurnal (1984), 18(11), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 11, pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of clomiphene citrate and some intermediates of its synthesis).
In this article the cis-isomer was isolated by fractional crystallization in petroleum ether. The evaporation of the mother liquors gave the trans-isomer with a purity of 86% (by GC). Repeated recrystallizations from hexane afforded analytic samples with a purity of 99%. This product was characterized by:
1H-NMR (C6D6) d 7.55-6.85 (m, 12H); 6.52 (m, 2H); 3.66 (t, 2H, —OCH2); 2.61 (t, 2H, CH2—N); 2.36 (q, 4H, 2xN-CH2)); 0.88 (t, 6H, 2xN—C—CH3)); Melting point 73-75° C.,
UV spectrum: λ max=242 nm, ε 21,600 and λ max 297 nm, ε 11,200.
Said known solid form of Enclomiphene base has the drawback that shows bad flowability, thus showing difficulties for passing through funnels (see example 22+19+FIG. 16). Said difficulties are magnified using and processing said material for the industrial manufacturing of:                Enclomiphene citrate using said Enclomiphene base as a chemical synthetic intermediate and/or        pharmaceutical products comprising said Enclomiphene.        
Moreover, the suspensions of said known solid form of Enclomiphene does not filter very well, i.e. for large productions, the filtering time can be very long and the product shows consequently a lower chemical purity, especially for the content of the Cis-Clomiphene impurity.